ABSTRACT Obstructive sleep apnea is a common disorder whose prevalence is linked to an epidemic of obesity in Western society. Sleep apnea is due to recurrent episodes of upper airway obstruction during sleep that are caused by elevations in upper airway collapsibility during sleep. Current evidence indicates that anatomic alterations and disturbances in upper airway neuromuscular control play key roles in the pathogenesis of obstructive sleep apnea. Obesity and particularly central adiposity are potent risk factors for sleep apnea. Our primary hypothesis is that metabolic and inflammatory dysregulation in obesity produce specific defects in upper airway mechanical and neuromuscular control during sleep. To address this hypothesis, human and murine models will be probed to characterize the mechanisms of upper airway dysfunction during sleep in obesity. Dramatic surgical weight loss and specific nocturnal interventions will be implemented to elucidate specific physiologic, metabolic and inflammatory mechanisms causing upper airway dysfunction during sleep (SA 1 & 2). Complementary murine experiments are proposed to establish specific adipocytokines and metabolic pathways in the pathogenesis of upper airway obstruction during sleep (SA3). An inter-disciplinary team will leverage scientific and institutional resources in this project to: (1) define distinct physiologic, metabolic and inflammatory mediators of sleep apnea susceptibility, and (2) lay the groundwork for targeting novel biomarkers and pathways for diagnostic and therapeutic purposes.